Several retinal diseases (particularly retinopathy of prematurity, diabetic retinopathy and sickle cell retinopathy) may result from oxidative damage since all occur under conditions of oxidative stress or hemorrhage. The neural retina is a highly oxygenated tissue and a prime site for free radical generation. It also contains a high level of polyunsaturated fatty acids, prime targets for free radical peroxidation. The generation of reactive oxygen species is catalyzed by transition metals, chiefly small iron complexes, but also by copper and heme. These may result from ischemia, hemorrhage or the normal mechanism of the transport of iron across the blood-retina barrier. Because of its sensitivity to free radical damage, the retina must possess protective mechanisms. Since this tissue is separated from the circulation by a barrier cell layer, protective plasma proteins are excluded from this tissue which may, therefore, contain sites of transition metal storage and synthesize its own protective proteins. The sites of metal deposition in the retina will be determined using cytochemistry and scanning electron microscopy combined with dispersive X-ray analysis. The control of synthesis of transferrin, hemopexin and other protective proteins such as haptoglobin which binds hemoglobin and metallothionein and superoxide dismutase which quench free radicals will be studied in vivo and in vitro under various conditions using Northern blots and polymerase chain reaction to detect messenger RNA levels together with in situ hybridizations to detect the sites of synthesis. Fluorescence techniques will be used to determine whether the presence of transition metals, oxidative stress and diabetes induces free radical generation in the retina. A common factor in the above retinopathies is angiogenesis which often leads to retinal traction. The mechanism of the induction of capillary growth by reactive oxygen species may involve locally produced growth factors. The possibility that certain cells in the retina produce such substances in situations of oxidative stress will be studied and the identification of the growth factors pursued. Elucidation of the role of reactive oxygen species in the retina together with the way in which the retina protects itself should indicate how these protective mechanisms become overwhelmed in retinopathy disease.